U.S. patent application number 16/601641 was filed with the patent office on 2020-04-16 for digital microfluidic delivery device.
The applicant listed for this patent is E INK CORPORATION. Invention is credited to Brian D. BEAN, Timothy J. O'MALLEY, Richard J. PAOLINI, JR., Stephen J. TELFER.
Application Number | 20200114135 16/601641 |
Document ID | / |
Family ID | 70159689 |
Filed Date | 2020-04-16 |
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United States Patent
Application |
20200114135 |
Kind Code |
A1 |
PAOLINI, JR.; Richard J. ;
et al. |
April 16, 2020 |
DIGITAL MICROFLUIDIC DELIVERY DEVICE
Abstract
An active molecule delivery system whereby active molecules can
be released on demand and/or a variety of different active
molecules can be delivered from the same system and/or different
concentrations of active molecules can be delivered from the same
system. The invention is well-suited for delivering pharmaceuticals
to patients transdermally. In some embodiments, the system includes
two separate reservoirs and a mixing area thereby allowing
precursors to be mixed immediately before transdermal delivery.
Inventors: |
PAOLINI, JR.; Richard J.;
(Framingham, MA) ; TELFER; Stephen J.; (Arlington,
MA) ; O'MALLEY; Timothy J.; (Westford, MA) ;
BEAN; Brian D.; (Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
E INK CORPORATION |
Billerica |
MA |
US |
|
|
Family ID: |
70159689 |
Appl. No.: |
16/601641 |
Filed: |
October 15, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62745718 |
Oct 15, 2018 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 35/10 20190501;
A61M 2205/0238 20130101; A61N 1/30 20130101; A61M 37/00 20130101;
A61M 2205/82 20130101; A61M 2037/0007 20130101 |
International
Class: |
A61M 35/00 20060101
A61M035/00 |
Claims
1. An active molecule delivery system comprising: a first substrate
comprising: a plurality of driving electrodes, a dielectric layer
covering the plurality of electrodes, and a first hydrophobic layer
covering the dielectric layer; a second substrate comprising: a
common electrode, a second hydrophobic layer covering the common
electrode; a spacer separating the first and second substrates and
creating a microfluidic region between the first and second
substrates; a porous diffusion layer coupled to the first substrate
on a side of the substrate opposed to the first hydrophobic layer,
wherein the first substrate comprises a passage providing fluidic
communication between the hydrophobic layer and the porous
diffusion layer; and a controller operatively coupled to the
driving electrodes and configured to provide a voltage gradient
between at least two driving electrodes.
2. The active molecule delivery system of claim 1, wherein each
driving electrode is coupled to a thin-film-transistor.
3. The active molecule delivery system of claim 1, further
comprising a plurality of passages providing fluidic communication
between the hydrophobic layer and the porous diffusion layer.
4. The active molecule delivery system of claim 1, wherein the
driving electrodes are flexible.
5. The active molecule delivery system of claim 1, wherein the
passage includes capillary tubes or wicking fibers.
6. The active molecule delivery system of claim 5, wherein the
capillary tubes or wicking fibers are coated with a hydrophobic
coating.
7. The active molecule delivery system of claim 1, further
comprising a reservoir in fluidic communication with the plurality
of driving electrodes.
8. The active molecule delivery system of claim 7, further
comprising a plurality of reservoirs in fluidic communication with
the plurality of driving electrodes, and a plurality of passages
providing fluidic communication between the hydrophobic layer and
the porous diffusion layer, wherein each reservoir is in fluidic
communication with only one passage.
9. The active molecule delivery system of claim 7, further
comprising a plurality of reservoirs and a mixing region in fluidic
communication with each of the plurality of reservoirs and the
passages providing fluidic communication between the hydrophobic
layer and the porous diffusion layer.
10. The active molecule delivery system of claim 1, wherein the
porous diffusion layer comprises acrylate, methacrylate,
polycarbonate, polyvinyl alcohol, cellulose,
poly(N-isopropylacrylamide) (PNIPAAm), polylactic-co-glycolic acid)
(PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon,
oriented polyester, terephthalate, polyvinyl chloride,
polyethylene, polybutylene, polypropylene, polyisobutylene, or
polystyrene.
11. The active molecule delivery system of claim 1, further
comprising a biocompatible adhesive in contact with the porous
diffusion layer.
12. A method for delivering an active molecule to the skin of a
subject, comprising: providing an active molecule delivery system
including: a first substrate comprising a plurality of driving
electrodes, a dielectric layer covering the plurality of
electrodes, and a first hydrophobic layer covering the dielectric
layer, a second substrate comprising a common electrode and a
second hydrophobic layer covering the common electrode, a spacer
separating the first and second substrates and creating a
microfluidic region between the first and second substrates, a
porous diffusion layer coupled to the first substrate on a side of
the substrate opposed to the first hydrophobic layer, wherein the
first substrate comprises a first passage providing fluidic
communication between the hydrophobic layer and the porous
diffusion layer, and a controller operatively coupled to the
driving electrodes and configured to provide a voltage gradient
between at least two driving electrodes; coupling the porous
diffusion layer to skin of a subject; moving a solution comprising
an active molecule from a driving electrode to the first passage
providing fluidic communication between the hydrophobic layer and
the porous diffusion layer; and allowing the active molecule to
pass from the porous diffusion layer to the skin of the
subject.
13. The method of claim 12, wherein the active molecule delivery
system further comprises a first reservoir in fluidic communication
with the plurality of driving electrodes, and wherein the solution
comprising an active molecule is held in the reservoir until the
solution comprising an active molecule is required for
delivery.
14. The method of claim 13, wherein the active molecule delivery
system further comprises a second reservoir and a second passage
providing fluidic communication between the hydrophobic layer and
the porous diffusion layer, wherein the first reservoir is only in
fluidic communication with the first passage and the second
reservoir is only in fluidic communication with the second
passage.
15. The method of claim 14, wherein the first reservoir contains a
first solution comprising the active molecule at a first
concentration and the second reservoir contains a second solution
comprising the active molecule at a second concentration.
16. The method of claim 13, wherein the active molecule delivery
system further comprises a second reservoir and a mixing area in
fluidic communication with both the first reservoir and the second
reservoir.
17. The method of claim 16, wherein the first reservoir contains a
first solution comprising a first precursor molecule and the second
reservoir contains a second solution comprising a second precursor
molecule, and wherein delivering an active molecule to the skin of
a subject further comprises: mixing the first precursor molecule
with the second precursor molecule to create a mixture; and moving
the mixture to the first passage providing fluidic communication
between the hydrophobic layer and the porous diffusion layer.
18. The method of claim 17, wherein the first precursor molecule is
an antibody.
19. The method of claim 17, wherein the first precursor is an
oligonucleotide.
20. The method of claim 17, wherein the mixture comprises an
opioid.
Description
RELATED APPLICATIONS
[0001] This application claims priority to co-pending U.S.
Provisional Patent Application No. 62/745,718, filed Oct. 15, 2018.
All patents, publications, and pending applications disclosed
herein are incorporated by reference in their entireties.
BACKGROUND
[0002] Digital microfluidic devices use independent electrodes to
propel, split, and join droplets in a confined environment, thereby
providing a "lab-on-a-chip." Digital microfluidic devices are
alternatively referred to as electrowetting on dielectric, or
"EWoD," to further differentiate the method from competing
microfluidic systems that rely on electrophoretic flow and/or
micropumps. A 2012 review of the electrowetting technology was
provided by Wheeler in "Digital Microfluidics," Annu. Rev. Anal.
Chem. 2012, 5:413-40, which is incorporated herein by reference in
its entirety. The technique allows sample preparation, assays, and
synthetic chemistry to be performed with tiny quantities of both
samples and reagents. In recent years, controlled droplet
manipulation in microfluidic cells using electrowetting has become
commercially viable; and there are now products available from
large life science companies, such as Oxford Nanopore.
[0003] Most of the literature reports on EWoD involve so-called
"passive matrix" devices (a.k.a. "segmented" devices), whereby ten
to twenty electrodes are directly driven with a controller. While
segmented devices are easy to fabricate, the number of electrodes
is limited by space and driving constraints. Accordingly, it is not
possible to perform massive parallel assays, reactions, etc. in
passive matrix devices. In comparison, "active matrix" devices
(a.k.a. active matrix EWoD, a.k.a. AM-EWoD) devices can have many
thousands, hundreds of thousands or even millions of addressable
electrodes. The electrodes are typically switched by thin-film
transistors (TFTs) and droplet motion is programmable so that
AM-EWoD arrays can be used as general purpose devices that allow
great freedom for controlling multiple droplets and executing
simultaneous analytical processes.
[0004] Because of the restrictive requirements on the electric
field leakage, most advanced AM-EWoD devices are constructed from
polycrystalline silicon (a.k.a. polysilicon., a.k.a. poly-Si).
However, polysilicon fabrication is substantially more expensive
than amorphous silicon fabrication, i.e., the type used in
mass-produced active matrix TFTs for the LCD display industry.
Polysilicon fabrication processes are more expensive because there
are unique handling and fabrication steps for working with
polysilicon. There are also fewer facilities worldwide that are
configured to fabricate devices from polysilicon. However, because
of the improved functionality of polysilicon, Sharp Corporation has
been able to achieve AM-EWoD devices that include propulsion,
sensing, and heating capabilities on a single active matrix. See,
e.g., U.S. Pat. Nos. 8,419,273, 8,547,111, 8,654,571, 8,828,336,
9,458,543, all of which are incorporated herein by reference in
their entireties. An example of a complex poly-Si AM-EWoD is shown
in FIG. 1.
[0005] Transdermal delivery of bioactive materials is
well-established technology. In the most straightforward
embodiments the biologically-active component (typically a molecule
having molecular weight below about 1000) is incorporated into a
polymeric matrix or gel that is placed into contact with a
patient's skin. Penetration of the molecule occurs by passive
diffusion, often over a period of several hours. The initiation of
drug delivery is by application of the patch to the skin. In the
current state of the art it is difficult to modulate the rate of
delivery of the active ingredient, however, from one particular
patch.
SUMMARY
[0006] The invention addresses this need by providing a low power
transdermal delivery system whereby the active molecules can be
loaded with a digital microfluidic platform and released on demand.
Additionally as described below, the invention provides a system
for delivering varying concentrations of active molecules from the
same delivery system at different times, and for delivering
multiple drugs at the same, or different, times from the same
patch.
[0007] The invention works by holding an active (i.e. a drug) in a
reservoir until it is needed and then it is moved to a porous
diffusion layer (e.g., a drug delivery gel) that is in contact with
the skin. In one aspect, the invention is an active molecule
delivery system comprising a first substrate, a second substrate, a
spacer, a porous diffusion layer and a controller. The first
substrate includes a plurality of driving electrodes, a dielectric
layer covering the plurality of electrodes, and a first hydrophobic
layer covering the dielectric layer. The second substrate includes
a common electrode, and a second hydrophobic layer covering the
common electrode. The spacer separates the first and second
substrates and creates a microfluidic region between the first and
second substrates. The porous diffusion layer is coupled to the
first substrate on a side of the substrate opposed to the first
hydrophobic layer, and the first substrate comprises a passage
providing fluidic communication between the hydrophobic layer and
the porous diffusion layer. The controller is operatively coupled
to the driving electrodes and configured to provide a voltage
gradient between at least two driving electrodes. The porous
diffusion layer may be constructed from a variety of materials,
such acrylate, methacrylate, polycarbonate, polyvinyl alcohol,
cellulose, poly(N-isopropylacrylamide) (PNIPAAm),
polylactic-co-glycolic acid) (PLGA), polyvinylidene chloride,
acrylonitrile, amorphous nylon, oriented polyester, terephthalate,
polyvinyl chloride, polyethylene, polybutylene, polypropylene,
polyisobutylene, or polystyrene. Typically, the reservoir has a
volume greater than 100 nL, and the porous diffusion layer has an
average pore size of between 1 nm and 100 nm. In some embodiments,
a device includes a plurality of passages. In some embodiments, the
passages include wicking materials such as capillary tubes or
fibers. In some embodiments, the porous diffusion layer is coupled
to a subject with a biocompatible adhesive.
[0008] Typically, the active molecule is a pharmaceutical compound;
however, systems of the invention can be used to deliver hormones,
nutraceuticals, proteins, nucleic acids, antibodies, or vaccines.
The invention may include a plurality of reservoirs and the device
may be configured to mix components prior to administering the
components. For example, it is possible to have different
reservoirs within the same device containing different mixtures or
similar mixtures having different concentrations. For example, a
system may include a first reservoir containing a mixture of first
active molecules and a second reservoir containing a mixture of
second active molecules, or a system may include a first reservoir
containing active molecules at a first concentration and a second
reservoir containing the same active molecules at a second
concentration. In other embodiments, the system may include a first
reservoir containing a mixture of active molecules and a second
reservoir containing an adjuvant and/or a skin penetrant. Other
combinations of active molecules, agents, and concentrations will
be evident to one of skill in the art.
[0009] The invention additionally includes a controller for
controlling an active molecule delivery system. This controller
includes an active molecule delivery system as described above,
that is, including a mixture of an active molecule dispersed in a
first charged phase and a second phase that is oppositely charged
or uncharged and immiscible with the first phase, or a mixture of
an active molecule and charged particles. The controller may also
include a switch configured to interrupt flow from the voltage
source to the active molecule delivery system. The switch may be a
mechanical switch or a digital switch, and the controller may
include a processor for controlling the switch. In some
embodiments, the controller will include a wireless receiver and a
wireless transmitter, thereby allowing the controller to be
interfaced with a device, such as a smart phone, docking station,
smart watch, fitness tracker, etc.
[0010] Devices of the invention can be used to deliver active
molecules to the skin of a subject. For example, using a device of
the invention a the porous diffusion layer can be coupled to the
skin of a subject, a solution comprising an active molecule can be
moved from a driving electrode to the first passage providing
fluidic communication between the hydrophobic layer and the porous
diffusion layer, and an active molecule allowed to pass from the
porous diffusion layer to the skin of the subject. In some
embodiments, the active is held in a first reservoir in fluidic
communication with the plurality of driving electrodes, and the
solution comprising an active molecule is held in the reservoir
until the solution comprising an active molecule is required for
delivery. In some embodiments, a device has two separate reservoirs
and a mixing area and an active molecule is delivered to a patient.
The first reservoir includes a first precursor solution, the second
reservoir includes a second precursor solution, and the delivery
function includes mixing the first precursor molecule with the
second precursor molecule to create a mixture and moving the
mixture to a passage providing fluidic communication between the
hydrophobic layer and the porous diffusion layer.
BRIEF DESCRIPTION OF DRAWINGS
[0011] FIG. 1 shows a prior art EWoD device including both
propulsion and sensing on the same active matrix.
[0012] FIG. 2 depicts the movement of an aqueous-phase droplet
between adjacent electrodes by providing differing charge states on
adjacent electrodes.
[0013] FIG. 3 depicts a cross-section of the invention when the
device is in an "off state" that is, the active has not been
loaded.
[0014] FIG. 4 depicts a cross-section of the invention when the
device is in an "on state" that is, the active has been loaded.
[0015] FIG. 5 is a plan view of a device of the invention including
a reservoir of active material, driving electrodes, passages and a
porous diffusion layer. FIG. 5 shows step-by-step (bottom to top)
dispensing a solution including an active molecule, moving the
droplets toward passages, movement to the passages, and dispensing
the droplets into the porous diffusion layer.
[0016] FIG. 6 illustrates a device of the invention wherein each
passage is coupled to only a single reservoir. In some embodiments,
each reservoir contains a different concentration of active
molecules, thereby allowing the dosage to be dynamically
controlled.
[0017] FIG. 7 illustrates a device of the invention whereby two
different reservoirs are coupled to a mixing area whereby two
components "A" and "B" can be mixed prior to delivery to the porous
diffusion layer.
[0018] FIG. 8 illustrates a delivery device of the invention
wherein the driving electrodes are flexible, thereby allowing the
delivery device to be wrapped around a limb, e.g., an arm or a
leg.
DETAILED DESCRIPTION
[0019] The invention provides an active molecule delivery system
whereby active molecules can be released on demand and/or a variety
of different active molecules can be delivered from the same system
and/or different concentrations of active molecules can be
delivered from the same system. The invention is well-suited for
delivering pharmaceuticals to patients transdermally, however the
invention may be used to deliver active ingredients to animals,
generally. The active delivery system includes a plurality of
reservoir(s), wherein the reservoir(s) are filled with a medium for
delivering the active molecules. In some embodiments the medium
includes active molecules dispersed in a first charged phase as
well as a second phase that is oppositely charged or uncharged and
immiscible with the first phase.
[0020] One molecule of interest for transdermal delivery is
naloxone, a competitive opioid receptor antagonist that is used to
prevent or reduce the effects of overdose of opioid narcotics.
Naloxone is poorly absorbed when taken by mouth and is typically
administered by injection or by means of nasal spray.
Unfortunately, the effects of the drug diminish after less than
about an hour, requiring the administration of several doses to
maintain therapeutic levels over long periods. Prior work has
suggested, however, that use of a transdermal patch of about 40
cm.sup.2 in area may be able maintain useful plasma concentrations
of naloxone over a period of about 4-48 hours. See, e.g.,
Panchagula, R., Bokalial, R.., Sharma, P. and Khandavilli, S
International Journal of Pharmaceutics, 293 (2005), 213-223. Thus,
a combination of an initial injected dose with a longer-acting
transdermal infusion might provide a practical means to maintain a
therapeutic concentration of naloxone while avoiding subjecting a
patient to multiple injections.
[0021] Military and civilian first responders, including
law-enforcement personnel, face the possibility of exposure to high
concentrations of opioid narcotics in dangerous situations in which
access to conventional medical care may be impossible. Ideally,
they would be able to self-administer an initial bolus of naloxone
(or a similar drug) and at the same time be able to trigger
longer-term release of a maintenance dose. It might in some
situations even be necessary that release of the drug be triggered
remotely, especially when the affected individual's ability to
function independently has been compromised. In these situations it
would be preferred to use a pre-applied transdermal patch in. a
state in which the drug to be delivered is in some way unavailable.
A triggering event would release the drug, allowing it to begin to
diffuse through the skin. Of course, delivery device are not
limited to these examples and can be used to deliver, e.g.,
hormones, nutraceuticals, proteins, nucleic acids, antibodies, or
vaccines.
[0022] Devices of the invention function by moving aqueous droplets
of actives using electrowetting on dielectric (EWoD). The
fundamental operation of an EWoD device is illustrated in the
sectional image of FIG. 2. The EWoD 200 includes a cell filled with
an oil 202 and at least one aqueous droplet 204. The cell gap is
typically in the range 50 to 200 .mu.m, but the gap can be larger.
In a basic configuration, as shown in FIG. 2, a plurality of
driving electrodes 205 are disposed on one substrate and a singular
top electrode 206 is disposed on the opposing surface. The cell
additionally includes hydrophobic coatings 207 on the surfaces
contacting the oil layer, as well as a dielectric layer 208 between
the driving electrodes 205 and the hydrophobic coating 207. (The
upper substrate may also include a dielectric layer, but it is not
shown in FIG. 2). The hydrophobic layer prevents the droplet from
wetting the surface. When no voltage differential is applied
between adjacent electrodes, the droplet will maintain a spheroidal
shape to minimize contact with the hydrophobic surfaces (oil and
hydrophobic layer). Because the droplets do not wet the surface,
they are less likely to contaminate the surface or interact with
other droplets except when that behavior is desired.
[0023] While it is possible to have a single layer for both the
dielectric and hydrophobic functions, such layers typically require
thick inorganic layers (to prevent pinholes) with resulting low
dielectric constants, thereby requiring more than 100V for droplet
movement. To achieve low voltage actuation, it is better to have a
thin inorganic layer for high capacitance and to be pinhole free,
topped by a thin organic hydrophobic layer. With this combination,
it is possible to have electrowetting operation with voltages in
the range +1-10 to +/-50V, which is in the range that can be
supplied by conventional TFT controllers.
[0024] When a voltage differential is applied between adjacent
electrodes, the voltage on one electrode attracts opposite charges
in the droplet at the dielectric-to-droplet interface, and the
droplet moves toward this electrode, as illustrated in FIG. 2. The
voltages needed for acceptable droplet propulsion depend on the
properties of the dielectric and hydrophobic layers. AC driving is
used to reduce degradation of the droplets, dielectrics, and
electrodes by various electrochemistries. Operational frequencies
for. EWoD can be in the range 100 Hz to 1 MHz, but lower
frequencies of 1 kHz or lower are preferred for use with TFTs that
have limited speed of operation.
[0025] FIG. 3 shows the principle of operation of an active
molecule delivery device 300 of the invention in cross-sectional
form (not to scale) when disposed upon skin 380. The device 300 is
constructed on one or more substrates 310/315, which may he a
flexible substrate. A common electrode 340 is spaced from a driving
electrode 345 by a spacer 330. The active molecule (drug) to be
delivered is dissolved in a water drop 320 suspended in an
incompatible solvent 325 (for example, a hydrocarbon, silicone, or
fluorinated organic oil). As discussed above, application of
appropriate voltages to the common electrode 340 and the driving
electrodes 345 can be used to move the water drop 320 laterally
toward the passage 360 which is coupled to the porous diffusion
layer 370 (from left to right). To facilitate movement of the water
drop 320, a hydrophobic layer 335 is provided below the common
electrode 340 and above the driving electrodes 345. A dielectric
layer 350 is intermediate between the hydrophobic layer 335 and the
driving electrodes 345.
[0026] A device of the invention includes one or more passages 360
(i.e., a channel in the z-direction), either through or adjacent to
a driving electrode 345. When a water drop 320 is positioned over
such a passage 360, as shown in FIG. 4, the active molecules can
move through the passage 360 to the porous diffusion layer 370 that
is in contact with the delivery surface, e.g., a patient's skin
380. At this location, diffusional contact is established between
the water droplets 320 and the porous diffusion layer 370 that is
in contact with the skin 380. Typically, the passage 360 will
include structures to facilitate movement of the solvent and active
mixture from the hydrophobic surface 335 to the porous diffusion
layer 370. For example, the passage may include materials that move
hydrophilic materials through capillary action, such as wicking
fibers, cellulose, or cotton. Such materials may be coated with an
additional hydrophobic coating to facilitate movement of the
aqueous solution from the electrowetting surface to the porous
diffusion layer 370. In some embodiments, a biocompatible adhesive
(not shown) may laminated to the porous diffusion layer. The
biocompatible adhesive will allow active molecules to pass through
while keeping the device immobile on a user. Suitable biocompatible
adhesives are available from 3M (Minneapolis, Minn.).
[0027] FIG. 5 shows a top view of an embodiment of an active
molecule delivery device 500 of the invention as if the top
electrode and the top substrate have been removed. The device 500
includes a substrate 515, driving electrodes 545, passages 560, and
a porous diffusion layer 570. The device additionally includes a
controller 543 that is coupled to the driving electrodes 545 with
traces 547. As shown in FIG. 5 a hydrophilic liquid containing a
target molecule (drug) to be delivered is located in a reservoir
590, i.e., a region of the device remote from the porous diffusion
layer that contacts the skin.
[0028] The sequence of delivery of a solution including an active
molecule is illustrated in FIG. 5 running from the bottom driving
electrodes to the top driving electrodes. Initially, droplets 520
are snapped off from the reservoir 590 thereby determining the
dosage that will be delivered
(concentration.times.volume.times.number of droplets). The droplets
520 are advanced until they are adjacent one or more passages 560,
whereupon an auxiliary driving electrode 548 that surrounds the
passage 560 is used to move the droplets 520 above the passages 560
using orthogonal electrowetting. Due to the wicking action of the
passage 560, the droplets 520 will move into and through the
passages 560 whereupon they are delivered to the porous diffusion
layer 570 below. Accordingly, the active ingredients in the
reservoir(s) 590 can be moved into the porous diffusion layer.
[0029] It is possible to imagine numerous different arrangements of
driving electrodes 545 with respect to the passages 560. In a
second embodiment, illustrated in FIG. 6, electrowetting forces are
used to withdraw fluid 620 from the reservoir 690 and transfer it
directly to a passage 660. The device 600 includes a substrate 615,
driving electrodes 645, passages 660, and a porous diffusion layer
670. The device additionally includes a controller 643 that is
coupled to the driving electrodes 645 with traces 647. No
orthogonal motion is needed in FIG. 6, however. Capillary forces,
provided by suitable materials between the driving electrodes 645
and the porous diffusion layer 670, withdraw fluid 620 from the
reservoir 690. While the fluid 620 is shown to be continuous, it is
to be understood that the fluid can be delivered in droplets as in
FIG. 5. As shown in FIG. 6, each passage 660 is coupled to a unique
reservoir 690. This allows each reservoir to act as a single dose,
thereby reducing the complexity of the system, e.g., whereby a
specific number of droplets of a specific volume of a specific
dosage must be snapped off and delivered. For example, a device 600
may include seven identical reservoirs and the controller 643
configured to administer the contents of one reservoir each morning
for seven consecutive days. Alternatively, different reservoirs 690
may each contain different concentrations of the same active so
that, for example, a subject can receive a first stronger dose of
the active and then receive one or more lower concentration
maintenance doses during the day. Such a device may be particularly
well suited for delivering hormones.
[0030] Another embodiment of the invention is shown in FIG. 7,
where the device 700 includes a substrate 715, driving electrodes
745, passages 760, and a porous diffusion layer 770. While a
controller is not shown, it is understood that a controller is
needed to coordinate functions of the driving electrodes 745. FIG.
7 illustrates that it is possible to do reactions "on chip" before
delivering an active molecule. As shown in FIG. 7, a first
reservoir "A" 791 and a second reservoir "B" 792 are both in
fluidic communication with a mixing area 793. A first precursor
molecule can be contained in a first solution in the first
reservoir 791 while a second precursor molecule can be contained in
a second solution in the second reservoir 792. Prior to
administering an active, the first solution and the second solution
are brought to the mixing area 793 where they are allowed to mix to
create the target active, which is then delivered to the porous
diffusion layer 770 in a method described above.
[0031] There are many advantages to a device 700 with the ability
to mix precursors prior to delivering a target active to the porous
diffusion layer 770. For example, the first precursor may be a
sensitive biologic, such as an antibody or an oligonucleotide that
must be stabilized for storage in a solution that is not suitable
for delivery through the porous diffusion layer. Accordingly, when
it is appropriate to deliver the biologic, an amount is transferred
from the first reservoir 791 to the mixing area 793 where the
biologic can be activated, cleaned, or targeted for delivery via
conjugation with promotors, markers, or other target specific
molecules). Such configurations may greatly increase the shelf life
of the biologics and they may allow a patient to avoid having to go
to a clinic to have the biologic delivered via intravenous
injection. In other alternatives, the first and second precursors
may be prodrugs that combine to create an opioid. Using a device of
the invention, it may he possible to prevent illegal opioid
administration because only users having the device and appropriate
security authorization could combine the precursors to create the
opioid.
[0032] The system of FIG. 7 may also be suitable for delivering
so-called "drug cocktails" that include active molecules that
deactivate each other over time and typically must be administered
in a clinic, e.g., a chemotherapy clinic. The system of FIG. 7 may
also be used to deliver, e.g,, a patient's own cells, antibodies,
etc. In such embodiments, the patient's own biological materials
may be held in a first reservoir and when it is appropriate to
deliver the therapeutic, the patient's own biological materials are
moved to the mixing area where they are combined with another
active ingredient prior to being delivered to the porous diffusion
layer.
[0033] The controller 543, 643, 743, may comprise a battery and
electronics required to initiate the electrowetting motion, and
means to communicate with the outside world such as appropriate
electronics/antenna, etc. In preferred arrangements, it will not be
possible to transfer drops of water containing the drug to the
passages without applying electrical signals. This will ensure that
the unactivated patch may be subjected to a variety of stresses
(mechanical, thermal, etc.) without releasing the active
ingredient.
[0034] In one embodiment, a device of the invention can be used to
deliver naloxone (NARCAN.TM.). The device would deliver about
20-100 mg of the drug from the reservoir to the porous diffusion
area. Assuming a near-saturated concentration of active (e.g.,
naloxone) in water in the reservoir of 50 mg/mL, the volume of
drops required to be delivered would be about 400-2000 .mu.L, which
is within the capability of the devices. In other embodiments,
devices of the invention can be used to deliver opioids, e.g.,
hydromorphone, hydrocodone, fentanyl, methadone, or oxycodone.
Devices of the invention may be used to deliver stimulants such as
nicotine, steroids (e.g., prednisone), and hormones (e.g.,
epinephrine).
[0035] In some embodiments, a device of the invention can be made
to be flexible so that the device can deployed on a curved surface
880 and/or integrated into a flexible package to improve user
comfort and compliance. An embodiment of such a device 800 is shown
in FIG. 8, whereby flexible drive electrodes 845 are coupled to a
porous diffusion layer 870 and passages 860 provide fluidic
communication between the drive electrodes 845 and the porous
diffusion layer 870. As shown in FIG. 8, the controller 843 and the
reservoir 890 may be combined into the same housing. In an
embodiment, the device 800 may take the shape of a wristband,
whereby the device 800 may be additionally augmented with
decorative designs to hide that the device 800 is, in fact, for
delivering drugs transdermally.
[0036] Advanced embodiments of an active molecule delivery system
will include circuitry to allow the active molecule delivery system
to be controlled wirelessly with a secondary device, such as a
smart phone or smart watch. With such improvements, a user can
control, for example, the type of active molecule that is delivered
and the amount that is delivered. Using an application on, e.g., a
smart phone or watch, it may be possible to program the device to
modify the amount of active molecule delivered based upon the time
of day. In other embodiments, the device may be operatively coupled
with biometric sensors, e.g., a fitness tracker or heart rate
monitor, whereby the application causes the dosage to be turned off
if, e.g., the pulse rate of the user exceeds a preset threshold.
Other embodiments may couple, e.g., a readout from a glucose
monitor to the device to allow for automatic delivery of insulin
when a patient is outside of their desired blood glucose level.
[0037] When desired, devices of the invention can be activated
and/or controlled remotely. For example, NFC, Bluetooth, WIFE, or
other wireless communication function may be used to activate a
device and cause the agent to be administered. Furthermore, the
same wireless communication may be used to monitor the performance
of the device, e.g., the percentage and area for all of the
reservoir(s) at different driving status is known, which means all
of the usage data will be available to a provider or therapist,
including when the patch is activated and what amount of active is
administered. For the "programmable" feature, because each
reservoir can be turned independently, the overall release profile
of the device can be programmed by driving differing concentrations
of actives or different actives from different reservoirs at
different times. Additionally, patient compliance is also good
because the smart device that is used to activate the patch can
also communicate with doctors remotely for data sharing.
[0038] It will be apparent to those skilled in the art that
numerous changes and modifications can be made in the specific
embodiments of the invention described above without departing from
the scope of the invention. Accordingly, the whole of the foregoing
description is to be interpreted in an illustrative and not in a
limitative sense.
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